Alzheimer's disease (AD) is a degenerative brain disorder characterized clinically by progressive loss of memory, cognition, reasoning, judgment and emotional stability that gradually leads to profound mental deterioration and ultimately death. AD is a very common cause of progressive mental failure (dementia) in aged humans and is believed to represent the fourth most common medical cause of death in the United States. AD begins slowly, first affecting the parts of the brain controlling thought, memory, and language. As symptoms worsen, patients may not remember family members, or have trouble speaking, reading, or writing. In later disease progression, AD patients may become anxious, aggressive, or wander away from home. Eventually needing total care, the AD patient may cause great stress for family members who care for them.
AD has been observed in all races and ethnic groups worldwide and presents a major present and future public health problem. As many as 4.5 million Americans suffer from AD. The disease usually begins after age sixty, and risk goes up with age. While younger people also may get AD, it is much less common. About five percent of men and women ages sixty-five to seventy-four have AD, and nearly half of those age eighty-five and older may have the disease. It is important to note, however, that AD is not a normal part of aging. AD is at present incurable. No treatment that effectively prevents AD or reverses its symptoms or course is currently known.
The deposition of amyloid-β (Aβ) peptides in the central nervous system in the form of amyloid plaques is one of the hallmarks of AD (U.S. Patent Publication No. 20040214774 to Wisniewski et al.; U.S. Pat. No. 6,114,133 to Seubert; Wegiel et al., “Alzheimer Dementia Neuropathology,” in Dementia: Presentations, Differential Diagnosis &Nosology, 89-120 (Emery & Oxman, eds., 2003). Several lines of evidence favor the conclusion that Aβ accumulation destroys neurons in the brain, leading to deficits in cognitive abilities. Because accumulation of Aβ appears to be the result of a shift in equilibrium from clearance toward deposition, identifying and promoting mechanisms that enhance Aβ clearance from the brain is highly desirable.
Vaccination was the first treatment approach which has been shown to have genuine impact on disease process, at least in animal models of AD (Sadowski et al., “Disease Modifying Approaches for Alzheimer's Pathology,” Current Pharmaceutic Design, 13:1943-54 (2007); Wisniewski et al., “Therapeutic Approaches for Prion and Alzheimer's Diseases,” FEBS J. 274:3784-98 (2007); Wisniewski et al., “Immunological and Anti-Chaperone Therapeutic Approaches for Alzheimer Disease,” Brain Pathol. 15:72-77 (2005)). Vaccination of AD transgenic (Tg) mice with Aβ1-42 or Aβ homologous peptides co-injected with Freund's adjuvant prevented the formation of Aβ deposition and as a consequence eliminate the behavioral impairments that are related to Aβ deposition (Schenk et al., “Immunization with Amyloid-Beta Attenuates Alzheimer-Disease-Like Pathology in the PDAPP Mouse,” Nature 400:173-77 (1999); Sigurdsson et al., “Immunization with a Nontoxic/Nonfibrillar Amyloid-beta Homologous Peptide Reduces Alzheimer's Disease-Associated Pathology in Transgenic Mice,” Am. J. Pathol. 159:439-47 (2001); Morgan et al., “A Beta Peptide Vaccination Prevents Memory Loss in an Animal Model of Alzheimer's Disease,” Nature 408:982-85 (2001); Janus et al., “A Beta Peptide Immunization Reduces Behavioural Impairment and Plaques in a Model of Alzheimer's Disease,” Nature 408:979-82 (2000)).
The striking biological effect of the vaccine in preclinical testing and the apparent lack of side effects in AD Tg mice encouraged Elan Pharmaceuticals, Inc./Wyeth Research to launch clinical trials with a vaccine designated as AN1792 which contained pre-aggregated Aβ1-42 and QS21 as an adjuvant. It was thought that this type of vaccine design would induce a strong adaptive cell mediated immune response, because QS21 is known to be a strong inducer of T-helper type-1 (Th-1) lymphocytes. The phase II of the trial was prematurely terminated when 6% of vaccinated patients manifested symptoms of acute meningoencephalitis. An autopsy performed on one of the affected patients revealed an extensive cytotoxic T-cell reaction surrounding some cerebral blood vessels. Analysis of the Aβ load in the brain cortex, however, suggested that Aβ clearance had occurred (Nicoll et al., “Neuropathology of Human Alzheimer Disease after Immunization with Amyloid-beta Peptide: A Case Report,” Nature Med. 9:448-52 (2003)). Neuropsychiatric testing of vaccinated patients who mounted an immune response showed a modest but statistically significant cognitive benefit, demonstrating an improvement on some cognitive testing scales comparing to baseline and a slowed rate of disease progression in patients who had developed antibodies to Aβ (Hock et al., “Antibodies Against Beta-Amyloid Slow Cognitive Decline in Alzheimer's Disease,” Neuron 38:547-54 (2003)). This indicated that the vaccination approach could be beneficial for human AD patients, but that the concept of the vaccine may need redesigning.
Given the significant impact of AD, there is a great need to discover, develop, and test new treatments that may be helpful in preventing and/or treating this devastating disease. The present invention is directed to achieve these objectives.